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Abstract: Triple-negative breast cancer (TNBC) is an aggressive tumor entity in which immune checkpoint (IC) molecules are primarily synthesized in the tumor environment. Here, we report that procoagulant platelets bear large amounts of such immunomodulatory factors and that the presence of these cellular blood components in TNBC relates to protumorigenic immune-cell activity and impaired survival. Mechanistically, tumor-released nucleic acids attract platelets to the aberrant tumor microvasculature, where they undergo procoagulant activation, thus delivering specific stimulatory and inhibitory IC molecules. This concomitantly promotes protumorigenic myeloid leukocyte responses and compromises antitumorigenic lymphocyte activity, ultimately supporting tumor growth. Interference with platelet-leukocyte interactions prevented immune cell misguidance and suppressed tumor progression, nearly as effective as systemic IC inhibition. Hence, our data uncover a self-sustaining mechanism of TNBC by using platelets to misdirect immune-cell responses. Targeting this irregular multicellular interplay may represent a novel immunotherapeutic strategy for TNBC without the adverse effects of systemic IC inhibition., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Dysregulated B cell responses have been described in inflammatory bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here provide evidence for the detrimental role of activated B cells during the onset of autoimmune intestinal inflammation. Using Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1 -/- ) mice as a mouse model of chronic colitis, we identified clusters of differentiation (CD)86 expression on activated B cells as a crucial factor exacerbating pro-inflammatory cytokine production of intestinal CD4 T cells. Depleting B cells through anti-CD20 antibody treatment or blocking costimulatory signals mediated by CD86 through cytotoxic T lymphocyte antigen-4-immunoglobulin (CTLA-4-Ig) diminished intestinal inflammation in our mouse model of chronic IBD at the onset of disease. This was due to a reduction in aberrant humoral immune responses and reduced CD4 T cell pro-inflammatory cytokine production, especially interferon-g (IFN-g) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, in addition to B cells isolated from the inflamed colon of Wipf1 -/- mice, we also found CD86 mRNA and protein expression upregulated on activated B cells isolated from inflamed tissue of human patients with IBD. B cell activation and CD86 expression were boosted by soluble CD40L in vitro, which we found in the serum of mice and human patients with IBD. In summary, our data provides detailed insight into the contribution of B cells to intestinal inflammation, with implications for the treatment of IBD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC., Methods: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans., Results: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis., Conclusions: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH., Impact and Implications: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Surgical residents prepare during their training for independent operating experience. However, there is a fine balance between supervised intraoperative teaching and the need to keep operations short since this is associated with improved patient safety. We aim to understand if the composition of the vascular surgical team-presence of anesthesia and surgical trainees as well as the number of circulating nurses-affects elective operative times at our institution. As a secondary aim, we analyzed how time of day affects overall operative time., Methods: We performed a retrospective review of all vascular surgery elective operations occurring between January 1, 2019, and October 15, 2021. Our reference operation between procedures was the construction of an arteriovenous fistula (AVF). Reference teams included circulating staff (fewer than two nurses), anesthesia (anesthesiologist with certified registered nurse anesthetist [CRNA]), and surgery (surgeon with nurse practitioner). The primary dependent variable was the time interval in minutes from wheels-in to wheels-out of surgery, which was divided into three subintervals: wheels-in to cut, cut to close, and close to wheels-out. Univariate analysis was performed to examine each surgical procedure's distribution of wheels-in to wheels-out time interval. Linear regression was performed to determine the effect of team composition and time of day on operative durations., Results: We included a total of 853 vascular operations. Regarding overall operative time, different procedures took various amounts of time compared with the reference operation (AVF creation). Amputations and arteriograms were shorter (-30 min, P = 0.03, and -12 min, P = 0.05, respectively). Other procedures were longer: endarterectomy (+48 min, P < 0.01), rib resection (+78 min, P < 0.01), endovascular aorta repair (+120 min, P < 0.01), lower extremity bypass (+170 min, P < 0.01), and open aortic repair (+410 min, P < 0.01). No significant difference was found in carotid artery stent placement. Overall, there was a significant reduction in the close to wheels-out interval for anesthesiologists with a trainee (mean: -2.4 min; 95%; CI: -4.7, -0.12; P = 0.04). AVF took significantly more time with a surgical resident: wheels-in to cut time (mean: +4.2 min; 95%; CI: 0.92, 7.4; P = 0.01) and cut to close time (mean: +13 min; 3.2, 23; P < 0.01). Arteriogram wheels-in to cut time took longer with a surgeon alone (mean: +5.6; 95%; CI: 0.29, 11; P = 0.04). There were no other statistically significant findings with change in composition of the surgical team or changes in start time., Conclusions: General surgery residents generally do not add time to vascular surgery cases but may do so in certain cases, perhaps when they are given more autonomy (i.e. AVF creation). Future studies should look at multiple centers, specific vascular procedures, and level of training to explore whether experience among residents (i.e., intern versus senior resident) and case complexity play a role in procedural length, as this may indirectly affect attending surgeon burnout and patient outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scorings have been reported to yield variable results in triple-negative breast cancer (TNBC). We compared the analytical concordance and reproducibility of four clinically relevant PD-L1 assays assessing immune cell (IC) score, tumor proportion score (TPS), and combined positive score (CPS) in TNBC. Primary TNBC resection specimens (n = 104) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28-8. PD-L1 expression was scored according to guidelines on virtual whole slide images by four trained readers. The mean PD-L1 positivity at IC-score ≥1% and CPS ≥1 ranged between 53% and 75% with the highest positivity for SP263 and comparable levels for 22C3, 28-8, and SP142. Inter-assay agreement was good between 28-8 and 22C3 across all scores and cut-offs (kappa 0.68-0.74) and for both assays with SP142 at IC-score ≥1% and CPS ≥1 (kappa 0.61-0.67). The agreement between SP263 and all other assays was substantially lower for all scores. Inter-reader agreement for each assay was good to excellent for IC-score ≥1% (kappa 0.73-0.78) and CPS ≥1 (kappa 0.68-0.74), fair to good for CPS ≥10 (kappa 0.52-0.67) and TPS ≥1% (kappa 0.53-0.72). The percentage of overlapping cases in the positive/negative category was >90% between IC-score ≥1% and CPS ≥1 but below when comparing IC-score ≥1% with CPS ≥10. We demonstrate an overall good inter-reader agreement for all PD-L1 assays in TNBC along with assay specific differences in positivity and concordances, which may aid to select the right test strategy in routine diagnostics., Competing Interests: Declaration of competing interest AN has attended Advisory Boards. DCW has received funding from Roche Pharma AG, BMS, and MSD. KSc has attended Advisory Boards and served as a speaker for Roche, MSD, and BMS. KS has received funding from Roche Pharma AG. MK has received remuneration from Springer Press, Biermann Press, Celgene, AstraZeneca, Myriad Genetics and Teva, received consultancy or advisory fees from Myriad Genetics, KVB, DKMS LIFE, BLÄK and TEVA, holds stock in Therawis Diagnostics GmbH and AIM GmbH and received funding from Sphingotec, Deutsche Krebshilfe, DFG, BMBF, the Senator Roesner Foundation and the Dr Pommer-Jung Foundation. DO is an employee of MSD Sharp & Dohme GmbH. WR has received funding from Roche Pharma AG, has attended Advisory Boards and served as a speaker for Roche, MSD, Novartis. WW has attended Advisory Boards, served as speaker for Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Amgen, Astellas, Illumina, Siemens, Agilent and Molecular Health and receives research funding from Roche, MSD, BMS and AstraZeneca. The remaining authors (SF, SK, AH) have no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T cells recognizing peptide-loaded MHC molecules. Herein, we report that virus-infected hepatocytes are also selectively eliminated through a cell-autonomous mechanism., Methods: We generated recombinant adenoviruses and genetically modified mouse models to identify the molecular mechanisms determining TNF-induced hepatocyte apoptosis in vivo and used in vivo bioluminescence imaging, immunohistochemistry, immunoblot analysis, RNAseq/proteome/phosphoproteome analyses, bioinformatic analyses, mitochondrial function tests., Results: We found that TNF precisely eliminated only virus-infected hepatocytes independently of local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NF-kB activation in healthy and infected hepatocytes, but selectively mediated apoptosis in infected hepatocytes. Caspase 8 activation downstream of TNF receptor signaling was dispensable for apoptosis in virus-infected hepatocytes, indicating an unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as the cause for this non-canonical induction of apoptosis through TNF. Mitochondria from virus-infected hepatocytes showed normal biophysical and bioenergetic functions but were characterized by reduced resilience to calcium challenge. In the presence of unchanged TNF-induced signaling, reactive oxygen species-mediated calcium release from the endoplasmic reticulum caused mitochondrial permeability transition and apoptosis, which identified a link between extrinsic death receptor signaling and cell-intrinsic mitochondrial-mediated caspase activation., Conclusion: Our findings reveal a novel concept in immune surveillance by identifying a cell-autonomous defense mechanism that selectively eliminates virus-infected hepatocytes through mitochondrial permeability transition., Lay Summary: The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Although canine pancreatic neuroendocrine neoplasms (PanNENs) have been proposed as a model for the counterpart human neoplasms, the type or grade of human PanNEN that they resemble is unclear. PanNENs in animals are classified as adenoma or carcinoma, whereas in humans they are classified as pancreatic neuroendocrine tumour (PanNET) if well-differentiated, or as pancreatic neuroendocrine carcinoma (PanNEC) if poorly differentiated. We evaluated 16 canine primary PanNENs and two metastases histologically and immunohistochemically, and graded them using the animal and human grading systems. All neoplasms had local or vascular invasion and were classified as pancreatic islet cell carcinomas according to the current WHO classification. The Ki-67 index was low in all cases (0.01-1.50%). All had cytoplasmic expression of synaptophysin and insulin but were immunonegative for glucagon, confirming a functional diagnosis of canine insulinoma. Membranous expression of SSTR2A and nuclear expression of ATRX, but no p53 expression, was found in all neoplasms. One primary tumour was diagnosed as a mixed neuroendocrine-non-neuroendocrine neoplasm, which is the first report of this neoplasm in dogs. The other 15 primary tumours and both metastatic tumours were graded as PanNET G1, according to the human WHO classification. We conclude that canine PanNENs share well-differentiated histomorphology, SSTR2A expression and absence of nuclear p53 immunolabelling with human PanNETs G1. However, they differ in ATRX gene expression and functionality, and seem to have a worse prognosis than human PanNETs G1, although their generally low Ki-67 index precludes more precise assessment of prognosis. Membranous SSTR2A expression renders canine PanNENs potentially amenable to treatment with somatostatin analogues or SSTR targeted in-vivo imaging methods., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest in relation to the research, authorship or publication of this article., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Adjuvant chemotherapy decision in patients with hormone receptor positive, HER2 negative breast cancer (BC) is challenging. Ki-67 is widely used for adjuvant therapy decision in BC. The multigene assay EndoPredict (EP) has shown to provide valid and additional information about the risk of recurrence compared to traditional pathological factors. In this study, we compared Ki-67 with EP assay generated risk groups., Methods: We analyzed the results from prospective EP testing (n = 373) and tumor proliferation assessed by Ki-67 staining in luminal breast cancer. We statistically investigated the association of both parameters and probed for equivalence in risk stratification., Results: Evaluation of Ki-67 was feasible in 307 (82%) BC specimens with known EP test results. The EPscore (now called 12-gene molecular score) delineated 140 low and 167 high scores. After combining the EPscore with pathological tumor stage and nodal status, we received 203 EPclin low-risk and 104 EPclin high-risk classifications. EPscore and EPclin were significantly associated with Ki-67 indices and tumor grade (p < 0.001). Overall, we observed a moderate correlation between Ki-67 and the EPscore (r = 0.63) as well as the EPclin score (r = 0.59)., Conclusion: Ki-67 values above 25% partly overlap with EP test results and therefore indicate a high-risk profile. In these cases, the additional prognostic information from EP testing might be rather low. However, low and intermediate Ki-67 values (less than 25%) alone were not reliable in predicting a low risk EP profile, indicating that EP testing is useful in this subgroup., Competing Interests: Declaration of competing interest JE received honoraria from Astra Zeneca, Roche, Celgene, Novartis, Lilly, Pfizer, Pierre Fabre, TEVA and travel support from Celgene, Pfizer, TEVA and Pierre Fabre. WW received research funding (Roche) and had consulting or advisory role (AZ, Roche, Takeda, Novartis, BMS, MSD). MK received remuneration from Springer Press, Biermann Press, Celgene, AstraZeneca, Myriad Genetics, and Teva, received consultancy or advisory fees from Myriad Genetics, KVB, DKMS LIFE, BLÄK, and TEVA, holds stock in Therawis Diagnostics GmbH and Busenfreundin GmbH, and received funding from Sphingotec, Deutsche Krebshilfe, DFG, Senator Roesner Foundation, and Dr. Pommer-Jung Foundation. The remaining authors (AN, SIA, AH, KS, KS, EK) have no competing interest to declare., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic carcinomas are rare in dogs and clinical signs are mostly non-specific. The literature on clinically and pathologically characterized canine exocrine pancreatic tumours is limited to 76 cases reported since 1963. This retrospective study analysed formalin-fixed samples of pancreatic carcinomas from 22 dogs, obtained during elective exploratory surgery (n = 16) or if the dog was humanely destroyed (n = 6). Tumours were diagnosed according to the World Health Organization classification of tumours of the pancreas of domestic animals. In seven cases, blood samples taken during or shortly before surgery were analysed for concentrations of alpha-amylase, 1,2-o-dilauryl-rac-glycero-3-glutaric acid-(6'-methylresorufin) ester lipase (DGGR lipase), C-reactive protein (CRP), alanine aminotransferase, glutamate dehydrogenase, alkaline phosphatase (ALP), canine trypsin-like immunoreactivity (cTLI) and canine pancreatic lipase immunoreactivity (cPLI). Neutrophil and lymphocyte numbers were determined as part of a complete blood count. Clinical signs were non-specific and included vomiting, inappetence and diarrhoea. Acinar carcinomas were most common (19/22) and observed growth patterns included: solid (n = 14), acinar (n = 5), clear cell (n = 3), mucinous (n = 2), trabecular (n = 1) or rosette-like (n = 1), occurring as a single pattern or in combination. Ductal carcinomas were identified in three cases. Pancreatitis was a common additional histological finding; five dogs had mild and nine dogs had severe pancreatitis. cPLI, DGGR lipase, cTLI and CRP were elevated in 5/5 acinar carcinomas. All liver enzymes were elevated in three of these five animals and ALP was increased in 4/5 dogs. Two dogs with ductal pancreatic carcinomas showed normal cPLI concentrations. One had increased CRP, liver enzymes and leucocytosis with neutrophilia, the other had elevated DGGR lipase and cTLI concentrations. Clinical findings in canine pancreatic carcinomas were non-specific and simultaneous inflammation can mask the detection of the underlying neoplasm in clinical examination and laboratory testing., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Intact epithelial barrier function is pivotal for maintaining intestinal homeostasis. Current therapeutic developments aim at restoring the epithelial barrier in inflammatory bowel disease. Histone deacetylase (HDAC) inhibitors are known to modulate immune responses and to ameliorate experimental colitis. However, their direct impact on epithelial barrier function and intestinal wound healing is unknown. In human and murine colonic epithelial cell lines, the presence of the HDAC inhibitors Givinostat and Vorinostat not only improved transepithelial electrical resistance under inflammatory conditions but also attenuated the passage of macromolecules across the epithelial monolayer. Givinostat treatment mediated an accelerated wound closure in scratch assays. In vivo, Givinostat treatment resulted in improved barrier recovery and epithelial wound healing in dextran sodium sulphate-stressed mice. Mechanistically, these regenerative effects could be linked to an increased secretion of transforming growth factor beta1 and interleukin 8, paralleled by differential expression of the tight junction proteins claudin-1, claudin-2 and occludin. Our data reveal a novel tissue regenerative property of the pan-HDAC inhibitors Givinostat and Vorinostat in intestinal inflammation, which may have beneficial implications by repurposing HDAC inhibitors for therapeutic strategies for inflammatory bowel disease.

Tumours of the exocrine pancreas are rare in cats and few cases are described in the literature. Cystic tumours of the pancreas are not included in the World Health Organization (WHO) international histological classification of tumours of domestic animals. The aim of this study was to characterize the pathology of primary epithelial tumours of the feline exocrine pancreas, with emphasis on cystic tumours. We reviewed tumours of the exocrine pancreas in 70 cats, including complete tumours or the entire pancreas (n = 18) and excisional biopsy samples of pancreatic tumours (n = 52). Macroscopically, the tumours were grouped as solid (n = 45) or cystic (n = 25). Solid tumours were subdivided into adenomas (n = 5) and carcinomas (n = 40) and cystic neoplasms into adenomas (n = 15), carcinomas (n = 7) and cases with diverse growth patterns (n = 3). All five grossly solid adenomas had acinar morphology, while the macroscopically solid carcinomas showed acinar (n = 17), tubular (n = 14) or mixed (n = 9) growth microscopically. Cystic adenomas had acinar (n = 2), tubular (n = 12) or mixed (n = 1) growth, while cystic carcinomas had exclusively tubular growth (n = 7). Three cases with cystic lesions showed diverse histopathological growth patterns. The clinical outcome was available in 57 cases. The majority of cats with carcinomas died or were humanely destroyed during or shortly after surgery (n = 32). However, 2/7 animals with cystic carcinomas showed longer survival times. Cats with cystic adenomas had survival times of up to 5 years. The results of this study show that cystic pancreatic tumours should be considered a differential diagnosis in cats with cystic intra-abdominal masses, even though these are not yet described in the WHO classification. Based on the relatively long survival times of cats with cystic adenomas, complete resection with subsequent histopathological examination is recommended., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a +/Cre ; Hes1 fl/fl ). Using this model, we studied the role of Hes1 in both acinar cell plasticity and pancreatic regeneration after caerulein-induced pancreatitis and in Kras G12D -driven PDAC development. We show that, although pancreatic development is not perturbed on the deletion of Hes1, terminal acinar differentiation in the adult pancreas is compromised. Moreover, the loss of Hes1 leads to the impaired regeneration of the exocrine compartment, accelerated fatty metaplasia, and persistent ADM after acute caerulein-induced pancreatitis. In Kras G12D -driven carcinogenesis, Hes1 ablation resulted in increased ADM, decreased formation of high-grade pancreatic intraepithelial neoplasias, and accelerated development of PDAC with shortened survival time. In conclusion, Hes1 plays a key role in acinar cell integrity and plasticity on cellular insults. Furthermore, Hes1 is an essential component of the pancreatic intraepithelial neoplasias-to-PDAC route in Kras G12D -driven mouse pancreatic carcinogenesis., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

A 16-year-old Friesian gelding with relapsing colic was humanely destroyed during diagnostic laparotomy due to suspected abdominal neoplasia. On post-mortem examination, the pancreas appeared as a firm mass (20 × 8 × 8 cm). The cut surface had a lobular structure with multiple cavities. Histological examination revealed severe chronic fibrosing pancreatitis with acinar-ductal metaplasia and duct dysplasia, which was considered to be the cause of the recurrent colic. Formation of tubular complexes within a background of acinar-ductal metaplasia is similar to the regressive lesions detected in the human pancreas in the context of inflammation, duct obstruction, cystic fibrosis and neoplasia. Pancreatic acinar-ductal metaplasia and ductal dysplasia are considered to be preneoplastic conditions in man and in the mouse., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Although spontaneous and medically induced canine embryonic or fetal death and "resorption" are clinically well documented, morphological studies of these processes are still missing. The objective of this study was therefore a detailed morphological investigation of canine placental sites after embryonic or fetal death. In five pregnant beagle bitches, embryonic or fetal death was induced by cloprostenol and cabergoline or by aglepristone. Two dogs served as untreated controls. Between Days 30 and 33 of gestation, the bitches were ovariohysterectomized, placental sites were fixed and examined by different methods. Morphological features of placental sites after both treatments were similar, finally leading to a complete disappearance of the placental labyrinth. Although there was an increase in the number of cells in the glandular chambers (superficial endometrial glands) expressing lysozyme after induced fetal death, signs of phagocytosis were absent in these cells, and no increased infiltration of maternal stroma by macrophages (compared to normal placental sites at the same time of gestation) occurred. We inferred that fetal and placental tissues were lysed, but no phagocytosis by genuine or "functional" macrophages was detectable. Further investigations are needed for a more detailed understanding of the morphological processes occurring after embryonic or fetal death in the dog.

In vivo confocal laser scanning microscopy (CLSM) represents a novel imaging tool that allows the examination of skin morphology in real time at a resolution equal to that of conventional microscopes. The aim of the study was to test the applicability of CLSM to the diagnostic discrimination of benign nevi and melanoma. five independent observers without previous experience in CLSM received a standardized instruction about diagnostic CLSM features. Subsequently, 117 melanocytic skin tumors (90 benign nevi and 27 melanoma), imaged using a commercially available, near-infrared, reflectance confocal laser scanning microscope, were evaluated by each observer. Overall, sensitivity of 88.15% and specificity of 97.60% was achieved by the five observers. Logistic regression analysis revealed that mainly cytomorphology, architecture and keratinocyte cell borders should be taken into account for diagnostic decisions. Remarkably, using the presence or absence of monomorphic melanocytes as a single diagnostic criterion, the classification results with a sensitivity of 98.15% and a specificity of 98.89% were superior to the intuitive, integrative judgement of the observers. This first sensitivity and specificity study with CLSM has yielded promising results. CLSM provides new and useful information to the clinician diagnosing melanocytic skin tumors.

Formalin-fixed, paraffin wax-embedded fetal membranes from 76 cases of equine abortion were examined immunohistochemically for equine herpesvirus (EHV)-1 antigen. Of the 76 cases, 11 had been proved EHV-1-positive by diagnostic methods applied to the aborted fetuses (viral isolation in tissue culture, or immunohistochemical examination, or both). Of the 11 fetal membranes from the virus-positive animals, five gave positive results on immunohistochemical examination, and three on in-situ hybridization; the positive signals were detected in trophoblastic cells and occasionally in monocytes and endothelial cells. The distribution of virus appeared to be related to areas of (1) vacuolar degeneration and desquamation of chorionic epithelium, (2) mild lympho-histiocytic vasculitis and placentitis, and (3) increased metabolic activity of mesenchymal cells in the villi of the fetal membranes. This is the first report of EHV-1 antigen and nucleic acid detection in the trophoblasts of fetal membranes from spontaneous cases of equine abortion.